Publications by authors named "Maria J Garcia"

74 Publications

Corneal Stroma Thickness Changes after Myopic Laser Corneal Refractive Surgery.

J Cataract Refract Surg 2021 Jul 27. Epub 2021 Jul 27.

Cornea, Cataract and Refractive Surgery Unit, Vissum Alicante, Spain. Division of Ophthalmology, School of Medicine, Universidad Miguel Hernández, Alicante, Spain. Watany Research & Development Center, Cairo, Egypt. Department of Structures, Construction and Graphical Expression, Technical University of Cartagena, Spain.

Purpose: To evaluate the postoperative behavior of the central corneal stroma thickness after myopic femto-LASIK and SMILE by using a combined anterior segment-OCT and placido disc topographer, and to compare the accuracy of both laser machines in predicting the real stromal change .

Setting: Vissum Miranza, Alicante, Spain.

Study Design: Prospective, observational, comparative study.

Methods: The Visumax-500kHz femtosecond laser (FS), and the Amaris-750 excimer laser were used for the correction of myopia with or without myopic astigmatism. Central and paracentral stromal thicknesses (ST) and 6mm-corneal aberrometry were obtained with the MS39 topographer. Laser predicted stromal consumption was recorded (maximum lenticule thickness for SMILE and central ablation depth for LASIK). Visual and refractive outcomes were also evaluated. Total follow-up was 6 months.

Results: 77 LASIK-eyes were matched with 77 SMILE-eyes. Mean preoperative spherical equivalent (SE) was -3.92±1.67D for LASIK and -4.02±1.63D for SMILE;p=0.356. After LASIK, ST parameters showed a significant rethickening between months 1-3 (+4.38µm for central-ST;p<0.001), remaining stable thereafter. After SMILE, all ST parameters remained stable from month-1. Stromal ablation prediction was higher for SMILE compared to LASIK for all SE ranges, although postoperatively such differences were significant only for ametropias≤4D. At 6 months, mean SMILE laser prediction error was -13.21±7.00µm, while LASIK prediction showed better accuracy (+0.92± 8.16µm; p<0.001).

Conclusions: The accuracy of the Amaris-750 excimer laser in predicting the stromal consumption after LASIK was better than the VisuMax-FS laser for SMILE. While SMILE stromal thicknesses remained stable from month-1, after LASIK a mild stromal rethickening was observed up to the third month.
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http://dx.doi.org/10.1097/j.jcrs.0000000000000765DOI Listing
July 2021

Identification of a Locus Near Associated With Progression-Free Survival in Ovarian Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Sep 23;30(9):1669-1680. Epub 2021 Jun 23.

Gynecologic Oncology Center, Kiel, Germany.

Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance.

Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy.

Results: We found seven SNPs at 12q24.33 associated with PFS ( < 5 × 10), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15-1.34; = 1.47 × 10). High expression of a nearby gene, , is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin .

Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. is a plausible candidate for the target of this association.

Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options..
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419101PMC
September 2021

Ruxolitinib for Severe COVID-19-Related Hyperinflammation in Nonresponders to Steroids.

Acta Haematol 2021 Jun 10:1-7. Epub 2021 Jun 10.

Hematology and Oncology Department, Clinical Hospital, Pontificia Universidad Católica de Chile, Santiago, Chile.

Introduction: Currently, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is a major public health problem worldwide. Although most patients present a mild infection, effective strategies are required for patients who develop the severe disease. Anti-inflammatory treatment with JAK inhibitors has been considered in SARS-CoV-2.

Methods: In this study, we presented our experience in a group of severe SARS-CoV-2 Chilean patients. This prospective study was performed on consecutive patients presenting severe respiratory failure owing to COVID-19 or high-risk clinical condition associated with SARS-CoV-2, and who were treated with ruxolitinib for management of associated inflammation. Overall, 18 patients presenting SARS-CoV-2 viral-induced hyperinflammation were treated with ruxolitinib, with 16 patients previously treated with steroids, 4 with tocilizumab, and 3 with both treatments.

Results: Ten patients evolved with favorable response, including 7 patients admitted with severe respiratory failure (PaFi less than 200 mm Hg in high-flow nasal cannula), presenting complete regression of hyperinflammation, regression of the lung lesions, and subsequent discharge. In the remaining 8 patients, 25% showed reduced inflammation, but early discharge was not achieved owing to the slow evolution of respiratory failure. Unfortunately, 3 patients demonstrated a severe respiratory failure. The early initiation of ruxolitinib was found to be associated with better clinical evolution (p < 0.005).

Conclusion: In this study, ruxolitinib resolved hyperinflammatory state in 55% of the patients, regardless of the previous steroid or tocilizumab therapy. Unfortunately, few patients demonstrated severe evolution despite ruxolitinib therapy. Notably, the treatment starting time appears to play an important role in achieving good outcomes. Further validation in randomized controlled trials is crucial.
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http://dx.doi.org/10.1159/000516464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339052PMC
June 2021

Multiple mutations in the EPSPS and ALS genes of Amaranthus hybridus underlie resistance to glyphosate and ALS inhibitors.

Sci Rep 2020 10 19;10(1):17681. Epub 2020 Oct 19.

Department of Agricultural Chemistry and Edaphology, University of Cordoba, 14071, Cordoba, Spain.

Amaranthus hybridus is one of the main weed species in Córdoba, Argentina. Until recently, this weed was effectively controlled with recurrent use of glyphosate. However, a population exhibiting multiple resistance (MR2) to glyphosate and imazamox appeared in a glyphosate resistant (GR) soybean field, with levels of resistance up to 93 and 38-fold higher to glyphosate and imazamox, respectively compared to the susceptible (S) population. In addition to imidazolinones, MR2 plants showed high resistance levels to sulfonylamino-carbonyl (thio) benzoates and moderate resistance to sulfonylureas and triazolopyrimidines. Multiple amino acid substitutions were found in both target genes, acetolactate synthase (ALS) and 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), responsible for conferring high herbicides resistance levels in this A. hybridus population. In the case of EPSPS, the triple amino acid substitution TAP-IVS was found. In addition, MR2 plants also showed increased EPSPS gene expression compared to susceptible plants. A Ser653Asn substitution was found in the ALS sequence of MR2, explaining the pattern of cross-resistance to the ALS-inhibitor herbicide families found at the ALS enzyme activity level. No other mutations were found in other conserved domains of the ALS gene. This is the first report worldwide of the target site resistance mechanisms to glyphosate and ALS inhibitors in multiple herbicide resistance Amaranthus hybridus.
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http://dx.doi.org/10.1038/s41598-020-74430-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572458PMC
October 2020

Tofacitinib in Ulcerative Colitis: Real-world Evidence From the ENEIDA Registry.

J Crohns Colitis 2021 Jan;15(1):35-42

Gastroenterology Department, Hospital General Universitario de Alicante and CIBERehd, Alicante, Spain.

Aim: To evaluate the effectiveness and safety of tofacitinib in ulcerative colitis [UC] in real life.

Methods: Patients from the prospectively maintained ENEIDA registry and treated with tofacitinib due to active UC were included. Clinical activity and effectiveness were defined based on Partial Mayo Score [PMS]. Short-term response/remission was assessed at Weeks 4, 8, and 16.

Results: A total of 113 patients were included. They were exposed to tofacitinib for a median time of 44 weeks. Response and remission at Week 8 were 60% and 31%, respectively. In multivariate analysis, higher PMS at Week 4 (odds ratio [OR] = 0].2; 95% confidence interval [CI] = 0].1-0.4) was the only variable associated with lower likelihood of achieving remission at Week 8. Higher PMS at Week 4 [OR = 0.5; 95% CI = 0.3-0.7] and higher PMS at Week 8 [OR = 0.2; 95% CI = 0.1-0.5] were associated with lower probability of achieving remission at Week 16. A total of 45 patients [40%] discontinued tofacitinib over time. Higher PMS at Week 8 was the only factor associated with higher tofacitinib discontinuation [hazard ratio = 1.5; 95% CI = 1.3-1.6]. A total of 34 patients had remission at Week 8; of these, 65% had relapsed 52 weeks after achieving remission; the dose was increased to 10 mg/12 h in nine patients, and five of them reached remission again. Seventeen patients had adverse events.

Conclusions: Tofacitinib is effective and safe in UC patients in real practice, even in a highly refractory cohort. A relevant proportion of patients discontinue the drug over time, mainly due to primary failure.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa145DOI Listing
January 2021

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.

Br J Cancer 2020 09 18;123(5):793-802. Epub 2020 Jun 18.

Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, England.

Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.

Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.

Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016).

Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
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http://dx.doi.org/10.1038/s41416-020-0900-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463007PMC
September 2020

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

Clin Cancer Res 2020 10 17;26(20):5411-5423. Epub 2020 Jun 17.

Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.

Purpose: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.

Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.

Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.

Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572656PMC
October 2020

Detection and Quantification of HspX Antigen in Sputum Samples Using Plasmonic Biosensing: Toward a Real Point-of-Care (POC) for Tuberculosis Diagnosis.

ACS Infect Dis 2020 05 14;6(5):1110-1120. Epub 2020 Apr 14.

Nanobiosensors and Bioanalytical Applications Group (NanoB2A), Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC, CIBER-BBN and BIST, Campus UAB, 08193 Barcelona, Spain.

Advancements that occurred during the last years in the diagnosis of (), the causative agent of tuberculosis infection, have prompted increased survival rates of patients. However, limitations related to the inefficiency of an early detection still remain; some techniques and laboratory methods do not have enough specificity and most instruments are expensive and require handling by trained staff. In order to contribute to a prompt and effective diagnosis of tuberculosis, we report the development of a portable, user-friendly, and low-cost biosensor device for its early detection. By using a label-free surface plasmon resonance (SPR) biosensor, we have established a direct immunoassay for the direct detection and quantification of the heat shock protein X (HspX) of , a well-established biomarker of this pathogen, directly in pretreated sputum samples. The method relies on highly specific monoclonal antibodies that are previously immobilized on the plasmonic sensor surface. This technology allows for the direct detection of the biomarker without amplification steps, showing a limit of detection (LOD) of 0.63 ng mL and a limit of quantification (LOQ) of 2.12 ng mL. The direct analysis in pretreated sputum shows significant differences in the HspX concentration in patients with tuberculosis (with concentration levels in the order of 116-175 ng mL) compared with non-tuberculosis infected patients (values below the LOQ of the assay).
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http://dx.doi.org/10.1021/acsinfecdis.9b00502DOI Listing
May 2020

Ethylene and Phloem Signals Are Involved in the Regulation of Responses to Fe and P Deficiencies in Roots of Strategy I Plants.

Front Plant Sci 2019 10;10:1237. Epub 2019 Oct 10.

Department of Agronomy, Campus de Excelencia Internacional Agroalimentario CeiA3, Universidad de Córdoba, Córdoba, Spain.

Iron (Fe) and phosphorus (P) are two essential mineral nutrients whose acquisition by plants presents important environmental and economic implications. Both elements are abundant in most soils but scarcely available to plants. To prevent Fe or P deficiency dicot plants initiate morphological and physiological responses in their roots aimed to specifically acquire these elements. The existence of common signals in Fe and P deficiency pathways suggests the signaling factors must act in conjunction with distinct nutrient-specific signals in order to confer tolerance to each deficiency. Previous works have shown the existence of cross talk between responses to Fe and P deficiency, but details of the associated signaling pathways remain unclear. Herein, the impact of foliar application of either P or Fe on P and Fe responses was studied in P- or Fe-deficient plants of , including mutants exhibiting altered Fe or P homeostasis. Ferric reductase and acid phosphatase activities in roots were determined as well as the expression of genes related to P and Fe acquisition. The results obtained showed that Fe deficiency induces the expression of P acquisition genes and phosphatase activity, whereas P deficiency induces the expression of Fe acquisition genes and ferric reductase activity, although only transitorily. Importantly, these responses were reversed upon foliar application of either Fe or P on nutrient-starved plants. Taken together, the results reveal interactions between P- and Fe-related phloem signals originating in the shoots that likely interact with hormones in the roots to initiate adaptive mechanisms to tolerate deficiency of each nutrient.
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http://dx.doi.org/10.3389/fpls.2019.01237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795750PMC
October 2019

The Triple Amino Acid Substitution TAP-IVS in the Gene Confers High Glyphosate Resistance to the Superweed .

Int J Mol Sci 2019 May 15;20(10). Epub 2019 May 15.

Department of Agricultural Chemistry and Edaphology, University of Cordoba, 14071 Cordoba, Spain.

The introduction of glyphosate-resistant (GR) crops revolutionized weed management; however, the improper use of this technology has selected for a wide range of weeds resistant to glyphosate, referred to as superweeds. We characterized the high glyphosate resistance level of an population (GRH)-a superweed collected in a GR-soybean field from Cordoba, Argentina-as well as the resistance mechanisms that govern it in comparison to a susceptible population (GSH). The GRH population was 100.6 times more resistant than the GSH population. Reduced absorption and metabolism of glyphosate, as well as gene duplication of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) or its overexpression did not contribute to this resistance. However, GSH plants translocated at least 10% more C-glyphosate to the rest of the plant and roots than GRH plants at 9 h after treatment. In addition, a novel triple amino acid substitution from TAP (wild type, GSH) to IVS (triple mutant, GRH) was identified in the EPSPS gene of the GRH. The nucleotide substitutions consisted of ATA, GTC and TCA instead of ACA, GCG, and CCA, respectively. The hydrogen bond distances between Gly-101 and Arg-105 positions increased from 2.89 Å (wild type) to 2.93 Å (triple-mutant) according to the EPSPS structural modeling. These results support that the high level of glyphosate resistance of the GRH population was mainly governed by the triple mutation TAP-IVS found of the EPSPS target site, but the impaired translocation of herbicide also contributed in this resistance.
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http://dx.doi.org/10.3390/ijms20102396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567628PMC
May 2019

Induced Systemic Resistance (ISR) and Fe Deficiency Responses in Dicot Plants.

Front Plant Sci 2019 11;10:287. Epub 2019 Mar 11.

Department of Botany, Ecology and Plant Physiology, Campus de Excelencia Internacional Agroalimentario CeiA3, Universidad de Córdoba, Córdoba, Spain.

Plants develop responses to abiotic stresses, like Fe deficiency. Similarly, plants also develop responses to cope with biotic stresses provoked by biological agents, like pathogens and insects. Some of these responses are limited to the infested damaged organ, but other responses systemically spread far from the infested organ and affect the whole plant. These latter responses include the Systemic Acquired Resistance (SAR) and the Induced Systemic Resistance (ISR). SAR is induced by pathogens and insects while ISR is mediated by beneficial microbes living in the rhizosphere, like bacteria and fungi. These root-associated mutualistic microbes, besides impacting on plant nutrition and growth, can further boost plant defenses, rendering the entire plant more resistant to pathogens and pests. In the last years, it has been found that ISR-eliciting microbes can induce both physiological and morphological responses to Fe deficiency in dicot plants. These results suggest that the regulation of both ISR and Fe deficiency responses overlap, at least partially. Indeed, several hormones and signaling molecules, like ethylene (ET), auxin, and nitric oxide (NO), and the transcription factor MYB72, emerged as key regulators of both processes. This convergence between ISR and Fe deficiency responses opens the way to the use of ISR-eliciting microbes as Fe biofertilizers as well as biopesticides. This review summarizes the progress in the understanding of the molecular overlap in the regulation of ISR and Fe deficiency responses in dicot plants. Root-associated mutualistic microbes, rhizobacteria and rhizofungi species, known for their ability to induce morphological and/or physiological responses to Fe deficiency in dicot plant species are also reviewed herein.
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http://dx.doi.org/10.3389/fpls.2019.00287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421314PMC
March 2019

Reduced Absorption and Impaired Translocation Endows Glyphosate Resistance in Amaranthus palmeri Harvested in Glyphosate-Resistant Soybean from Argentina.

J Agric Food Chem 2019 Jan 17;67(4):1052-1060. Epub 2019 Jan 17.

Departamento de Quimica , Universidade Federal de São Carlos , 13565-905 São Carlos , Brazil.

Amaranthus palmeri S. Watson is probably the worst glyphosate-resistant (GR) weed worldwide. The EPSPS (5-enolpyruvylshikimate-3-phosphate-synthase) gene amplification has been reported as the major target-site-resistance (TSR) mechanism conferring resistance to glyphosate in this species. In this study, TSR and non-target-site-resistance (NTSR) mechanisms to glyphosate were characterized in a putative resistant A. palmeri population (GRP), harvested in a GR soybean crop from Argentina. Glyphosate resistance was confirmed for the GRP population by dose-response assays. No evidence of TSR mechanisms, as well as glyphosate metabolism, was found in this population. Moreover, a susceptible population (GSP) that absorbed about 10% more herbicide than the GRP population was evaluated at different periods after treatment. The GSP population translocated about 20% more glyphosate to the remainder of the shoots and roots at 96 h after treatment than the control, while the GRP population retained 62% of herbicide in the treated leaves. This is the first case of glyphosate resistance in A. palmeri involving exclusively NTSR mechanisms.
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http://dx.doi.org/10.1021/acs.jafc.8b06105DOI Listing
January 2019

A Shoot Fe Signaling Pathway Requiring the OPT3 Transporter Controls GSNO Reductase and Ethylene in Roots.

Front Plant Sci 2018 11;9:1325. Epub 2018 Sep 11.

Department of Agronomy, Campus de Excelencia Internacional Agroalimentario, Universidad de Córdoba, Córdoba, Spain.

Ethylene, nitric oxide (NO) and glutathione (GSH) increase in Fe-deficient roots of Strategy I species where they participate in the up-regulation of Fe acquisition genes. However, -nitrosoglutathione (GSNO), derived from NO and GSH, decreases in Fe-deficient roots. GSNO content is regulated by the GSNO-degrading enzyme -nitrosoglutathione reductase (GSNOR). On the other hand, there are several results showing that the regulation of Fe acquisition genes does not solely depend on hormones and signaling molecules (such as ethylene or NO), which would act as activators, but also on the internal Fe content of plants, which would act as a repressor. Moreover, different results suggest that total Fe in roots is not the repressor of Fe acquisition genes, but rather the repressor is a Fe signal that moves from shoots to roots through the phloem [hereafter named LOng Distance Iron Signal (LODIS)]. To look further in the possible interactions between LODIS, ethylene and GSNOR, we compared WT Columbia and LODIS-deficient mutant plants subjected to different Fe treatments that alter LODIS content. The mutant is impaired in the loading of shoot Fe into the phloem and presents constitutive expression of Fe acquisition genes. In roots of both Columbia and plants we determined 1-aminocyclopropane-1-carboxylic acid (ACC, ethylene precursor), expression of ethylene synthesis and signaling genes, and GSNOR expression and activity. The results obtained showed that both 'ethylene' (ACC and the expression of ethylene synthesis and signaling genes) and 'GSNOR' (expression and activity) increased in Fe-deficient WT Columbia roots. Additionally, Fe-sufficient roots had higher 'ethylene' and 'GSNOR' than Fe-sufficient WT Columbia roots. The increase of both 'ethylene' and 'GSNOR' was not related to the total root Fe content but to the absence of a Fe shoot signal (LODIS), and was associated with the up-regulation of Fe acquisition genes. The possible relationship between GSNOR(GSNO) and ethylene is discussed.
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http://dx.doi.org/10.3389/fpls.2018.01325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142016PMC
September 2018

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

J Pathol Clin Res 2018 10 21;4(4):250-261. Epub 2018 Sep 21.

Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
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http://dx.doi.org/10.1002/cjp2.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174617PMC
October 2018

Whole-genome sequence analysis of the Mycobacterium avium complex and proposal of the transfer of Mycobacterium yongonense to Mycobacterium intracellulare subsp. yongonense subsp. nov.

Int J Syst Evol Microbiol 2018 Jun 23;68(6):1998-2005. Epub 2018 Apr 23.

Departamento de Medicina Preventiva y Salud Publica y Microbiologia, Universidad Autonoma de Madrid, Madrid, Spain.

Bacterial whole-genome sequences contain informative features of their evolutionary pathways. Comparison of whole-genome sequences have become the method of choice for classification of prokaryotes, thus allowing the identification of bacteria from an evolutionary perspective, and providing data to resolve some current controversies. Currently, controversy exists about the assignment of members of the Mycobacterium avium complex, as is for the cases of Mycobacterium yongonense and 'Mycobacterium indicus pranii'. These two mycobacteria, closely related to Mycobacterium intracellulare on the basis of standard phenotypic and single gene-sequences comparisons, were not considered a member of such species on the basis on some particular differences displayed by a single strain. Whole-genome sequence comparison procedures, namely the average nucleotide identity and the genome distance, showed that those two mycobacteria should be considered members of the species M. intracellulare. The results were confirmed with other whole-genome comparison supplementary methods. According to the data provided, Mycobacterium yongonense and 'Mycobacterium indicus pranii' should be considered and renamed and included as members of M. intracellulare. This study highlights the problems caused when a novel species is accepted on the basis of a single strain, as was the case for M. yongonense. Based mainly on whole-genome sequence analysis, we conclude that M. yongonense should be reclassified as a subspecies of Mycobacterium intracellulareas Mycobacterium intracellularesubsp. yongonense and 'Mycobacterium indicus pranii' classified in the same subspecies as the type strain of Mycobacterium intracellulare and classified as Mycobacterium intracellularesubsp. intracellulare.
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http://dx.doi.org/10.1099/ijsem.0.002767DOI Listing
June 2018

Laser-Assisted in Situ Keratomileusis with Optimized, Fast-Repetition, and Cyclotorsion Control Excimer Laser to Treat Hyperopic Astigmatism with High Cylinder.

Eur J Ophthalmol 2017 Nov;27(6):686-693

1 Cornea, Cataract and Refractive Surgery Unit, Vissum Corporación, Alicante - Spain.

Purpose: To evaluate the visual outcomes after femtosecond laser-assisted laser in situ keratomileusis (LASIK) surgery to correct primary compound hyperopic astigmatism with high cylinder using a fast repetition rate excimer laser platform with optimized aspheric profiles and cyclotorsion control.

Methods: Eyes with primary simple or compound hyperopic astigmatism and a cylinder power ≥3.00 D had uneventful femtosecond laser-assisted LASIK with a fast repetition rate excimer laser ablation, aspheric profiles, and cyclotorsion control. Visual, refractive, and aberrometric results were evaluated at the 3- and 6-month follow-up. The astigmatic outcome was evaluated using the Alpins method and ASSORT software.

Results: This study enrolled 80 eyes at 3 months and 50 eyes at 6 months. The significant reduction in refractive sphere and cylinder 3 and 6 months postoperatively (p<0.01) was associated with an improved uncorrected distance visual acuity (p<0.01). A total of 23.75% required retreatment 3 months after surgery. Efficacy and safety indices at 6 months were 0.90 and 1.00, respectively. At 6 months, 80% of eyes had an SE within ±0.50 D and 96% within ±1.00 D. No significant differences were detected between the third and the sixth postoperative months in refractive parameters. A significant increase in the spherical aberration was detected, but not in coma. The correction index was 0.94 at 3 months.

Conclusions: Laser in situ keratomileusis for primary compound hyperopic astigmatism with high cylinder (>3.00 D) using the latest excimer platforms with cyclotorsion control, fast repetition rate, and optimized aspheric profiles is safe, moderately effective, and predictable.
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http://dx.doi.org/10.5301/ejo.5001051DOI Listing
November 2017

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci.

Oncotarget 2017 Sep 15;8(39):64670-64684. Epub 2017 Jun 15.

Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that and are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, and expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (<1×10). Larger patient numbers will be needed to convincingly identify any true associations at these loci.
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http://dx.doi.org/10.18632/oncotarget.18501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630285PMC
September 2017

Characterisation of the novel deleterious RAD51C p.Arg312Trp variant and prioritisation criteria for functional analysis of RAD51C missense changes.

Br J Cancer 2017 Sep 22;117(7):1048-1062. Epub 2017 Aug 22.

Human Genetics Group, Spanish National Cancer Research Center, C/Melchor Fernández Almagro 3, Madrid 28029, Spain.

Background: Despite a high prevalence of deleterious missense variants, most studies of RAD51C ovarian cancer susceptibility gene only provide in silico pathogenicity predictions of missense changes. We identified a novel deleterious RAD51C missense variant (p.Arg312Trp) in a high-risk family, and propose a criteria to prioritise RAD51C missense changes qualifying for functional analysis.

Methods: To evaluate pathogenicity of p.Arg312Trp variant we used sequence homology, loss of heterozygosity (LOH) and segregation analysis, and a comprehensive functional characterisation. To define a functional-analysis prioritisation criteria, we used outputs for the known functionally confirmed deleterious and benign RAD51C missense changes from nine pathogenicity prediction algorithms.

Results: The p.Arg312Trp variant failed to correct mitomycin and olaparib hypersensitivity and to complement abnormal RAD51C foci formation according to functional assays, which altogether with LOH and segregation data demonstrated deleteriousness. Prioritisation criteria were based on the number of predictors providing a deleterious output, with a minimum of 5 to qualify for testing and a PredictProtein score greater than 33 to assign high-priority indication.

Conclusions: Our study points to a non-negligible number of RAD51C missense variants likely to impair protein function, provides a guideline to prioritise and encourage their selection for functional analysis and anticipates that reference laboratories should have available resources to conduct such assays.
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http://dx.doi.org/10.1038/bjc.2017.286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625680PMC
September 2017

Characterization of -Like Strains by Comparative Genomics.

Front Microbiol 2017 8;8:789. Epub 2017 May 8.

Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São PauloSão Paulo, Brazil.

Isolates of the - complex are subdivided into four clusters (CHI to CHIV) in the INNO-LiPA® spp DNA strip assay. A considerable phenotypic variability was observed among isolates of the CHII cluster. In this study, we examined the diversity of 26 CHII cluster isolates by phenotypic analysis, drug susceptibility testing, whole genome sequencing and single-gene analysis. Pairwise genome comparisons were performed using several approaches, including average nucleotide identity (ANI) and genome-to-genome distance (GGD) among others. Based on ANI and GGD the isolates were identified as (14 isolates), (2 isolates) and (1 isolate). The remaining 9 isolates were subdivided into three novel putative genomospecies. Phenotypic analyses including drug susceptibility testing, as well as whole genome comparison by TETRA and delta differences, were not helpful in separating the groups revealed by ANI and GGD. The analysis of standard four conserved genomic regions showed that alone and the concatenated sequences clearly distinguished the taxonomic groups delimited by whole genome analyses. In conclusion, the CHII INNO-LiPa is not a homogeneous cluster; on the contrary, it is composed of closely related different species belonging to the complex and also several unidentified isolates. The detection of these isolates, putatively novel species, indicates a wider inner variability than the presently known in this complex.
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http://dx.doi.org/10.3389/fmicb.2017.00789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420552PMC
May 2017

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Nat Genet 2017 May 27;49(5):680-691. Epub 2017 Mar 27.

N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
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http://dx.doi.org/10.1038/ng.3826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612337PMC
May 2017

Detection of a Putative TetR-Like Gene Related to BCG Growth in Cholesterol Using a -Transposon Mutagenesis System.

Front Microbiol 2017 6;8:315. Epub 2017 Mar 6.

Departamento de Medicina Preventiva, Universidad Autónoma Madrid, Spain.

transposition is a powerful genetic tool for identifying mycobacterial virulence genes and studying virulence factors in relation to the host. Transposon shuttle mutagenesis is a method for constructing stable insertions in the genome of different microorganisms including mycobacteria. Using an IS derivative, we have constructed the Tn, a transposon containing a promoterless green fluorescent protein () gene. This transposon was able to transpose randomly in BCG. Bacteria with a single copy of the gene per chromosome from an BCG::Tngfp library were analyzed and cells exhibiting high levels of fluorescence were detected by flow cytometry. Application of this approach allowed for the selection of a mutant, BCG_2177c::Tn (BCG-Tn), on the basis of high level of long-standing fluorescence at stationary phase. This BCG-Tn mutant showed some particular phenotypic features compared to the wild type strain, mainly during stationary phase, when cholesterol was used as a sole carbon source, thus supporting the relationships of the targeted gene with the regulation of cholesterol metabolism in this bacteria. This approach showed that Tn is a potentially useful tool for studying the involvement of the targeted loci in metabolic pathways of mycobacteria.
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http://dx.doi.org/10.3389/fmicb.2017.00315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337628PMC
March 2017

COMBINED INTRAVITREAL RANIBIZUMAB AND ORAL SUPPLEMENTATION WITH DOCOSAHEXAENOIC ACID AND ANTIOXIDANTS FOR DIABETIC MACULAR EDEMA: Two-Year Randomized Single-Blind Controlled Trial Results.

Retina 2017 Jul;37(7):1277-1286

*Department of Ophthalmology, Hospital Universitario Morales Meseguer, Murcia, Spain †Faculty of Health Sciences, San Antonio Catholic University of Murcia, Murcia, Spain; and ‡Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.

Purpose: To assess the 2-year effectiveness of intravitreal ranibizumab combined with a dietary supplement rich in docosahexaenoic acid (DHA) plus antioxidants in 62 patients with diabetic macular edema.

Methods: In a randomized single-blind controlled study, 33 subjects (42 eyes) received intravitreal ranibizumab alone and 29 (34 eyes) combined with DHA (1,050 mg/day). Monthly ranibizumab (0.5 mg) was given for the first 4 months followed by on as-needed treatment.

Results: At 24 months, the difference between groups in the decrease of central subfield macular thickness was significant in favor of the DHA supplementation group (95% confidence interval of the difference 7.20-97.656; P = 0.024), although improvement in best-corrected visual acuity measured in the Early Treatment Diabetic Retinopathy Study letters did not reach statistical significance (95% confidence interval 5.4-11.2, P < 0.66). At 24 months, gains of >5 and >10 letters were significantly higher in the DHA supplementation group as compared with controls when the worse and better seeing eyes were considered but other differences at 12 months and 24 months were not found.

Conclusion: Intravitreal ranibizumab combined with DHA supplementation reduced central subfield macular thickness after 2 years of follow-up as compared with ranibizumab alone in patients with diabetic macular edema. This anatomical improvement was accompanied by a trend for an amelioration of vision.
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http://dx.doi.org/10.1097/IAE.0000000000001363DOI Listing
July 2017

Biological control of AFB1-producing Aspergillus section Flavi strains isolated from brewer's grains, alternative feed intended for swine production in Argentina.

J Environ Sci Health B 2016 Jul 12;51(7):477-81. Epub 2016 Apr 12.

a Department of Microbiology and Immunology , National University of Río Cuarto , Río Cuarto , Córdoba , Argentina.

The aim of the present study was to investigate the inhibitory activity of lactic acid bacteria (LAB) isolated from brewer's grains on Aspergillus section Flavi growth and aflatoxin B1 production. The Aspergillus strains tested were inhibited by all the LAB strains assayed. The isolates Lactobacillus brevis B20, P. pentosaceus B86, Lactococcus lactis subsp. lactis B87, L. brevis B131, and Lactobacillus sp. B144 completely suppressed the fungal growth and reduced aflatoxin B1 production. In conclusion, LAB isolated from brewer's grains show a high inhibitory activity on fungal growth and aflatoxin biosynthesis by Aspergillus flavus and Aspergillus parasiticus. Further studies must be conducted to evaluate the success of in vitro assays under food environment conditions and to elucidate the antifungal mechanism of these strains.
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http://dx.doi.org/10.1080/03601234.2016.1159460DOI Listing
July 2016

Editorial Commentary: Do We Have Strategies to Improve the Preventive Treatment of Latent Tuberculosis Infection?

Clin Infect Dis 2016 06 6;62(11):1401-2. Epub 2016 Mar 6.

Department of Preventive Medicine and Public Health and Microbiology, School of Medicine, Autonoma University of Madrid, Spain.

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http://dx.doi.org/10.1093/cid/ciw132DOI Listing
June 2016

Gene and whole genome analyses reveal that the mycobacterial strain JS623 is not a member of the species Mycobacterium smegmatis.

Microb Biotechnol 2016 Mar 1;9(2):269-74. Epub 2016 Feb 1.

Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.

Unexpected differences were found between the genome of strain JS623, used in bioremediation studies, and the genome of strain mc(2) 155, a model organism for investigating basic biology of mycobacteria. Both strains are currently assigned in the databases to the species Mycobacterium smegmatis and, consequently, the environmental isolate JS623 is increasingly included as a representative of that species in comparative genome-based approaches aiming at identifying distinctive traits of the different members of the genus Mycobacterium. We applied traditional molecular taxonomic procedures--inference of single and concatenated gene trees--to re-evaluate the membership of both strains to the same species, adopting the latest accepted cut-off values for species delimitation. Additionally, modern whole genome-based in silico methods where performed in a comprehensive molecular phylogenetic analysis of JS623 and other members of the genus Mycobacterium. These analyses showed that all relevant genome parameters of JS623 clearly separate this strain from M. smegmatis. The strain JS623 should be corrected as Mycobacterium sp. not only in the literature but, even more importantly, in the database entries, as inclusion of the genome wrongly attributed to the M. smegmatis species in comparative studies will result in misleading conclusions.
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http://dx.doi.org/10.1111/1751-7915.12336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767285PMC
March 2016

Ethylene Participates in the Regulation of Fe Deficiency Responses in Strategy I Plants and in Rice.

Front Plant Sci 2015 27;6:1056. Epub 2015 Nov 27.

Department of Botany, Ecology and Plant Physiology, University of Córdoba Córdoba, Spain.

Iron (Fe) is very abundant in most soils but its availability for plants is low, especially in calcareous soils. Plants have been divided into Strategy I and Strategy II species to acquire Fe from soils. Strategy I species apply a reduction-based uptake system which includes all higher plants except the Poaceae. Strategy II species apply a chelation-based uptake system which includes the Poaceae. To cope with Fe deficiency both type of species activate several Fe deficiency responses, mainly in their roots. These responses need to be tightly regulated to avoid Fe toxicity and to conserve energy. Their regulation is not totally understood but some hormones and signaling substances have been implicated. Several years ago it was suggested that ethylene could participate in the regulation of Fe deficiency responses in Strategy I species. In Strategy II species, the role of hormones and signaling substances has been less studied. However, in rice, traditionally considered a Strategy II species but that possesses some characteristics of Strategy I species, it has been recently shown that ethylene can also play a role in the regulation of some of its Fe deficiency responses. Here, we will review and discuss the data supporting a role for ethylene in the regulation of Fe deficiency responses in both Strategy I species and rice. In addition, we will review the data about ethylene and Fe responses related to Strategy II species. We will also discuss the results supporting the action of ethylene through different transduction pathways and its interaction with other signals, such as certain Fe-related repressive signals occurring in the phloem sap. Finally, the possible implication of ethylene in the interactions among Fe deficiency responses and the responses to other nutrient deficiencies in the plant will be addressed.
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http://dx.doi.org/10.3389/fpls.2015.01056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661236PMC
December 2015

The mycobacterial iron-dependent regulator IdeR induces ferritin (bfrB) by alleviating Lsr2 repression.

Mol Microbiol 2015 Dec 18;98(5):864-77. Epub 2015 Sep 18.

Public Health Research Institute at New Jersey Medical School, Rutgers State University of New Jersey, 225 Warren Street, Newark, NJ, 07103, USA.

Emerging evidence indicates that precise regulation of iron (Fe) metabolism and maintenance of Fe homeostasis in Mycobacterium tuberculosis (Mtb) are essential for its survival and proliferation in the host. IdeR is a central transcriptional regulator of Mtb genes involved in Fe metabolism. While it is well understood how IdeR functions as a repressor, how it induces transcription of a subset of its targets is still unclear. We investigated the molecular mechanism of IdeR-mediated positive regulation of bfrB, the gene encoding the major Fe-storage protein of Mtb. We found that bfrB induction by Fe required direct interaction of IdeR with a DNA sequence containing four tandem IdeR-binding boxes located upstream of the bfrB promoter. Results of in vivo and in vitro transcription assays identified a direct repressor of bfrB, the histone-like protein Lsr2. IdeR counteracted Lsr2-mediated repression in vitro, suggesting that IdeR induces bfrB transcription by antagonizing the repressor activity of Lsr2. Together, these results elucidate the main mechanism of bfrB positive regulation by IdeR and identify Lsr2 as a new factor contributing to Fe homeostasis in mycobacteria.
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http://dx.doi.org/10.1111/mmi.13166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879814PMC
December 2015

HspX knock-out in Mycobacterium tuberculosis leads to shorter antibiotic treatment and lower relapse rate in a mouse model--a potential novel therapeutic target.

Tuberculosis (Edinb) 2015 Jan 20;95(1):31-6. Epub 2014 Nov 20.

Institute of Infection and Immunity, St George's, University of London, United Kingdom.

Effective global tuberculosis control is hindered by the need for prolonged chemotherapy which leads to poor patient compliance. Therefore novel drug targets that shorten the duration of chemotherapy and reduce disease relapse rates are highly desirable. We have previously shown that HspX, an alpha-crystallin-like protein, is associated with growth suppression of Mycobacterium tuberculosis in mouse models. We determined to evaluate hspX as a novel target for controlling M. tuberculosis growth in combination with traditional antibiotic therapy in the Cornell mouse model. The hspX deletion mutant (ΔhspX) was used as a model of potential hspX inhibition. Normal BALB/c mice were infected with ΔhspX or the wild type (WT) strain. Three weeks after infection, the mice were treated with rifampicin, isoniazid and pyrazinamide for 14 weeks followed by 8 weeks of hydrocortisone. The effect of chemotherapy was measured by organ bacterial counts and the relapse rate. Antibiotic treatment of mice infected with ΔhspX resulted in faster visceral clearance; organs were disease free 8 weeks post-treatment for ΔhspX infection compared to 14 weeks for the WT strain. Disease relapse rate was significantly lower in ΔhspX infection (60.7%) compared to WT infection (92.6%). HspX may be a promising therapeutic target in combination with traditional antibiotic therapy to shorten the length of treatment and reduce disease relapse.
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http://dx.doi.org/10.1016/j.tube.2014.11.002DOI Listing
January 2015

Deletion at 6q24.2-26 predicts longer survival of high-grade serous epithelial ovarian cancer patients.

Mol Oncol 2015 Feb 5;9(2):422-36. Epub 2014 Oct 5.

Human Genetics Group, Spanish National Cancer Research Center (CNIO), C/ Melchor Fernández Almagro 3, 28029, Madrid, Spain; Biomedical Network Research Centre on Rare Diseases (CIBERER), Spain. Electronic address:

Standard treatments for advanced high-grade serous ovarian carcinomas (HGSOCs) show significant side-effects and provide only short-term survival benefits due to disease recurrence. Thus, identification of novel prognostic and predictive biomarkers is urgently needed. We have used 42 paraffin-embedded HGSOCs, to evaluate the utility of DNA copy number alterations, as potential predictors of clinical outcome. Copy number-based unsupervised clustering stratified HGSOCs into two clusters of different immunohistopathological features and survival outcome (HR = 0.15, 95%CI = 0.03-0.81; Padj = 0.03). We found that loss at 6q24.2-26 was significantly associated with the cluster of longer survival independently from other confounding factors (HR = 0.06, 95%CI = 0.01-0.43, Padj = 0.005). The prognostic value of this deletion was validated in two independent series, one consisting of 36 HGSOCs analyzed by fluorescent in situ hybridization (P = 0.04) and another comprised of 411 HGSOCs from the Cancer Genome Atlas study (TCGA) (HR = 0.67, 95%CI = 0.48-0.93, Padj = 0.019). In addition, we confirmed the association of low expression of the genes from the region with longer survival in 799 HGSOCs (HR = 0.74, 95%CI = 0.61-0.90, log-rank P = 0.002) and 675 high-FIGO stage HGSOCs (HR = 0.76, 95%CI = 0.61-0.96, log-rank P = 0.02) available from the online tool KM-plotter. Finally, by integrating copy number, RNAseq and survival data of 296 HGSOCs from TCGA we propose a few candidate genes that can potentially explain the association. Altogether our findings indicate that the 6q24.2-26 deletion is an independent marker of favorable outcome in HGSOCs with potential clinical value as it can be analyzed by FISH on tumor sections and guide the selection of patients towards more conservative therapeutic strategies in order to reduce side-effects and improve quality of life.
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http://dx.doi.org/10.1016/j.molonc.2014.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528660PMC
February 2015
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